Oxytocin is a mammalian hormone, secreted by the posterior pituitary gland, that acts primarily as a neuromodulator in the brain. Oxytocin plays an important role in the neuroanatomy of intimacy, specifically during and after childbirth. It is released in large amounts after distension of the cervix and uterus during labour, facilitating childbirth, maternal bonding and lactation.
Oxytocin is a peptide of nine amino acids (a nonapeptide). Its systematic name is cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide. Its half-life in the blood is typically about three minutes. Oxytocin has a molecular mass of 1007.19 g/mol. One international unit (IU) of oxytocin is the equivalent of about 1.68 micrograms of pure peptide.
Oxytocin as a drug is often used to induce labour and support labour in case of non-progression of parturition and to treat obstetric hemorrhage. Obstetric hemorrhage is estimated to cause 25% of all maternal deaths and is the leading direct cause of maternal mortality worldwide. Postpartum hemorrhage (PPH), defined as vaginal bleeding in excess of 500 ml after delivery, accounts for most cases of obstetric hemorrhage. It occurs in more than 10% of all births and is associated with a 1% case fatality rate.
Although active management of the third stage of labour (AMTSL) can prevent up to 60% of PPH cases, PPH continues to have a devastating impact on women in low-resource settings where home births are common and health care facilities are often inaccessible. Obstetric hemorrhage accounts for 34% of maternal deaths in Africa, 31% in Asia, and 21% in Latin America and the Caribbean. Among women who do survive PPH, approximately 12% will have severe anemia. Also, women who survive severe PPH (greater than 1,000 ml of blood loss) are significantly more likely to die during the following year.
Injectable oxytocin (intravenously or intramuscularly) has been recommended by the World Health Organization (WHO) for routine use during AMTSL and is the preferred drug for the prevention and management of blood loss after childbirth. Administering the injection, however, requires skill, sterilized equipment, and proper disposal of medical waste. Oral administration of oxytocin is not a suitable route of administration, since the peptide oxytocin is degraded in the gastrointestinal tract.
At present, oxytocin is available only as a liquid formulation in single-dose vials of 10 IU for intramuscular (IM) or intravenous (IV) injection. Four other preparations under investigation are at various stages of development and introduction (Uterotonic Research and Policy Agenda for Reducing Mortality and Morbidity Related to Postpartum Hemorrhage. A consensus statement issued by the participants in the meeting on “The Role of Uterotonics in Reducing Postpartum Hemorrhage: What Next?”, held on 4-5 Oct. 2011 in The Hague, The Netherlands). These preparations are:    a) oxytocin delivered IM via a Uniject® device packaged with a Time Temperature Indicator (TTI);    b) a more heat-stable liquid oxytocin formulation;    c) lyophilized heat-stable oxytocin reconstituted with sterile water for IM or IV injection;    d) a heat-stable powdered oxytocin formulation for aerosol delivery and inhalation.
In 1993 and 1994, WHO-supported studies demonstrated that oxytocin loses potency in field conditions, particularly tropical climates. Depending on the manufacturer and regulatory agency specification, all oxytocin products must be stored in either controlled room temperature (25° C. or lower) or refrigerated storage (2° C. to 8° C.) to ensure quality.
In third world countries, it is often practically and/or economically impossible to protect pharmaceutical preparations from the harmful effects of high temperatures and high humidity during transportation, storage and use. Besides stability in high temperature and humidity conditions, pharmaceutical preparations for use in tropical climates must fulfill extra requirements, such as a simple route of administration and untrained people should be able to administer the pharmaceutical preparation safely.
Carbetocin is a long-acting synthetic octapeptide having an action very similar to oxytocin. Carbotecin is also used as an obstetric drug to control postpartum hemorrhage and bleeding after giving birth. The commercially available carbetocin formulation PABAL® (100 μg/ml solution for injection, Ferring Pharmaceuticals Ltd.) is not stable at room temperature and requires refrigerated storage at a temperature of 2-8° C.
Atosiban is a synthetic nonapeptide and is an inhibitor of oxytocin and vasopressin. It is used as an intravenous medication as a labour repressor (tocolytic) to halt premature labour. Atosiban is available as a lyophilized (freeze dried) powder that should be stored desiccated below −18° C. At room temperature lyophilized atosiban is stable for 3 weeks.
Recently a lot a scientific research has been performed to study what causes the degradation of oxytocin in aqueous solutions.
Hawe et al. (Pharm Res. 2009 July; 26(7): 1679-1688) observed that the degradation of oxytocin strongly depends on the pH of the formulation, with the highest stability at pH 4.5.
Recent studies describe new strategies to stabilize oxytocin in aqueous solutions. Avanti et al. (The AAPS Journal. 2011; 13(2):284-290) and Avanti et al. (Int J Pharm. 2013 Feb. 28; 444(1-2):139-45) suggested that stability of oxytocin in aqueous solution can be improved by addition of divalent metal ions in combination with a citrate or aspartate buffer, respectively.
WO 2010/030180 mentions that the stability of aqueous peptide formulations, containing small therapeutic Cys-containing peptides such as oxytocin, is greatly enhanced by the presence of a buffer and at least one non-toxic source of divalent metal ions in a concentration of at least 2 mM.
WO 2012/042371 describes a pharmaceutical liquid composition, comprising carbetocin or pharmaceutically active salt thereof, and having pH between 5.0 and 6.0. This liquid composition may be stored at room temperature (e.g. at 25° C. and 60% relative humidity) for a sustained period (e.g. up to 2 years). The examples of the international patent application described liquid aqueous formulations containing carbetocine, buffer and anti-oxidant (methionine and/or EDTA).
A recent publication (http://path.org/publications/files/TS_oxytocin_fdt_for_pph_pos.pdf) describes a proposal for a project that aims to develop a heat-stable, fast-dissolving oxytocin tablet for sublingual administration. Several potential advantages of such a sublingual oxytocin tablet vis-à-vis existing oxytocin preparations for intramuscular injection or intravenous infusion are listed.
Sublingual tablets containing oxytocin have been marketed in the past (brand names Pitocin® and Syntocinon®). These products have been withdrawn from the market as greater control in induction and augmentation of labour could be achieved by intravenous or intramuscular administration of oxytocin. Sublingual administration was considered to be more unpredictable and in addition the pharmacokinetic profile showed an unfavorable latent period. Also, the sublingual tablets were not stable enough under tropical conditions.
De Groot et al. (J. of Pharm. Pharmacol. 1995, 47; 571-575) describe a study in which bioavailability and pharmacokinetics of sublingual oxytocin (Pitocin® tablet) was investigated. The study showed substantial inter-individual variability in bioavailability of oxytocin. The authors conclude that sublingual administration of oxytocin does not seem a reliable route for immediate prevention of PPH due to ‘long’ lag time and ‘long’ absorption half-life.
De Groot et al. (J. of Clinical Pharmacy and Therapeutics, 1995, 20, 115-119) describe experiments wherein the effect of simulated tropical conditions on buccal oxytocin tablets (tablet components not specified) was studied. The conclusion was that tropical conditions make oxytocin tablets unstable, with humidity as the most adverse factor. The oxytocin tablets were partially protected from the harmful effect of humidity by sealed aluminum package.
There remains a need for an oxytocin formulation for in-mouth (e.g. sublingual or buccal) administration that has good bioavailability and pharmacokinetics, that does not require refrigerated storage, that can be administered by untrained people and that can be manufactured and distributed at low cost. This same need exists for carbetocin and atosiban, especially since currently formulations for in-mouth administration of carbetocin or atosiban are not commercially available.